eLife Assessment

This theoretical study makes a useful contribution to our understanding of a subtype of type 2 diabetes - ketosis-prone diabetes mellitus (KPD) - with a potential impact on our broader understanding of diabetes and glucose regulation. The article presents an ordinary differential equation-based model for KPD that incorporates a number of distinct timescales - fast, slow, as well as intermediate, incorporating a key hypothesis of reversible beta cell deactivation. The presented evidence is solid and shows that observed clinical disease trajectories may be explained by a simple mathematical model in a particular parameter regime.

eLife Assessment

The findings are important and intriguing, with theoretical or practical implications beyond a single subfield. The computational methods employed are clever and sophisticated and the strength of evidence is convincing. Both the hypotheses and the exploratory nature of additional analyses are clearly stated.

eLife Assessment

Argunşah et al. investigate the mechanisms underlying the differential response dynamics of barrel vs septa domains in shaping the responses to single vs multiple whiskers. Based on the observation of a higher density of SST+ interneurons in the septa, the authors investigate the hypothesis that Elfn1-dependent short-term plasticity shapes these responses. This important study is, however, supported by incomplete evidence; factors restricting the strength of evidence are the limited spatial resolution of the multi-unit activity, as well as the lack of a mechanistic explanation. This provocative and intellectually stimulating hypothesis provides a contribution to work on how different cell types shape cortical representation.

eLife Assessment

This important study reports that the human posterior inferotemporal cortex (hPIT) functions as an attentional priority map, integrating both top-down and bottom-up attentional signals rather than serving solely as an object-processing region. The experiments and analyses are well conducted and provide convincing evidence that hPIT bridges dorsal and ventral attention networks and is robustly modulated by attention across diverse visual tasks. The study will be relevant for researchers investigating visual attention, high-level visual cortex, and the neural mechanisms that integrate endogenous and exogenous attentional control.

eLife Assessment

This study provides important findings on the neural circuits underlying dishabituation of the olfactory avoidance response in Drosophila. The data as presented provide solid evidence that the dishabituation involves distinct pathways from habituation. They show that reward-activated dopaminergic neurons provide input for within-modal dishabituation, while punishment-activated dopaminergic neurons provide input for cross-modal dishabituation. The work will interest neuroscientists, particularly behavioral neuroscientists working on habituation, neural circuits, and the dopaminergic system.

eLife Assessment

This manuscript presents a valuable computational tool for identifying 3-5 gene regulatory network topologies capable of generating oscillatory dynamics. The application of Monte Carlo Tree Search to circuit design is novel and effectively expands the scale at which non-linear behaviours can be explored in silico. The efficiency of the proposed algorithm is convincing, and the work will be of interest to the systems and synthetic biology communities. While the evolutionary implications remain unclear, the methodological contribution represents a significant advance in the field.

eLife Assessment

This useful study reports findings that support the use of the Open Field Test in Drosophila as a model to study "emotion-like states", which are behavioral responses to several stressful or aversive treatments, and resilience upon their subsequent removal. Behavioral data, by employing established stress-causing treatments and genetic manipulations, are solid. While the results and conceptual framework of this work will be of interest to behaviorists regardless of animal models, the novelty of this work over previous studies could have been clearer.

eLife Assessment

This important study demonstrates the significance of incorporating biological constraints in training neural networks to develop models that make accurate predictions under novel conditions. By comparing standard sigmoid recurrent neural networks (RNNs) with biologically constrained RNNs, the manuscript offers compelling evidence that biologically grounded inductive biases enhance generalization to perturbed conditions. This manuscript will appeal to a wide audience in systems and computational neuroscience.

eLife Assessment

This useful study attempts to place an ancient maize sample from Bolivia, dated to the end of the Incan empire, in genetic and geographical context. The analyses show that this sample is most closely related to ancient Peruvian maize, but the data are inadequate to determine the direction of dispersal. There are additional deficiencies in the statistical analyses and selection inferences. The topic of the study would appeal to researchers studying maize dispersal and adaptation.

eLife Assessment

This important study provides a novel approach for delineating subcortical-cortical white matter bundles. The authors provide convincing evidence by harnessing state-of-the-art methods and cross-species data. Together, this effort will be of interest to scientists across multiple subfields.

eLife Assessment

This valuable work presents how PRDM16 plays a critical role during colloid plexus development, through regulating BMP signaling. Solid evidence supports the context-dependent gene regulatory mechanisms both in vivo and in vitro. The work will be of broad interest to researchers working on growth factor signaling mechanisms and vertebrate development.

eLife Assessment

In this valuable study, Roiuk et al combined ribosome profiling and reporter assays to provide compelling evidence that eIF2A does not have a major impact on mRNA translation in HeLa cells. These findings are consistent with several recent publications that disaffirm the previously proposed role of eIF2A in directing protein synthesis under stress. Considering that stress-dependent perturbations in translation play a major role in homeostasis and several pathological states (e.g., cancer and neurological disorders), this work should be of broad interest to researchers studying regulation of gene expression, stress-adaptation, cancer and neurobiology.

eLife Assessment

This important manuscript by Genzoni et al. reports the striking discovery of a regulatory role for trophic eggs in ant caste determination. Prior to this study, trophic eggs were widely assumed to play only a nutritional role in the colony, but this compelling study shows that trophic eggs can suppress queen development, and therefore regulate caste determination in specific social contexts.

eLife Assessment

This study reports useful information on the mechanisms by which a high-fat diet induces arrhythmias in the model organism Drosophila. Specifically, the authors propose that adipokinetic hormone (Akh) secretion is increased with this diet, and through binding of Akh to its receptor on cardiac neurons, arrhythmia is induced. The authors have revised their manuscript but the evidence remains incomplete. Nonetheless, the data presented will be helpful to those who wish to extend the research to a more complex model system, such as the mouse.

eLife Assessment

This study provides fundamental information on how Arg-II participates in cardiac aging. The phenotypic data provide convincing evidence of non-cell-autonomous contributions to aging-related pathologies. Overall, the study highlights the importance of intercellular signaling in maintaining cardiac health during aging.

eLife Assessment

The findings represent an important contribution to understanding whether BMI influences head and neck cancer (HNC) risk after accounting for tobacco use. Within the context of the Mendelian Randomization (MR) field, the strength of evidence appears convincing, supported by rigorous methods and a thorough exploration of multiple genetic models of adiposity using diverse MR approaches. Limitations include the absence of associations in sensitivity models designed to better account for pleiotropy, which prevents evaluation of whether incorporating an instrumental variable for tobacco use would alter the findings. Additionally, the lack of a formal power assessment for detecting associations with the instrumental variables employed limits the interpretability and reach of the results.

eLife Assessment

This study identifies novel approaches to improving transgene expression in the injured mammalian myocardium through a combination of a tissue regeneration enhancer element and engineered AAVs - specifically, a liver-detargeting capsid, AAV.cc84, and an in vivo library screen-selected AAV-IR41. The evidence is convincing, and the AAV vectors are of fundamental value to the field of cardiac gene therapy. Future research exploring how to combine the features of AAV.cc84 and AAV-IR41 could yield an even more promising vector for therapeutic use.

eLife Assessment

This valuable study concerns a model for transgenerational epigenetic inheritance, the learned avoidance by C. elegans of the PA14 pathogenic strain of Pseudomonas aeruginosa. A recent study questioned whether transgenerational inheritance in this paradigm lacks robustness. The authors of this study have worked independently of the group that reported the original phenomenon and also independently of the group that challenged the original report. With solid data, this study independently validates findings previously reported by the Murphy group, confirming that the paradigm is reproducible elsewhere. The present study is therefore of broad interest to anyone studying genetics, epigenetics, or learned behavior.

eLife Assessment

This study presents a useful finding showing that the high susceptibility to sepsis of Kit-mutant mice is due to dysbiosis. However, the data provided is incomplete and would benefit from more rigorous approaches. With the mechanism part strengthened, this paper would be of interest to researchers on mast cell biology and mucosal immunology.

eLife Assessment

This study provides important insights into the role of polyUbiquitination in neurodegenerative diseases, elucidating how pUb promotes neurodegeneration by affecting proteasomal function. The findings not only offer a new perspective on the pathophysiology of neurodegenerative diseases but also provide potential targets for developing new therapeutic strategies. The results provide solid evidence to support the conclusions.

eLife Assessment

This important study, which has been improved further upon revision, reveals a critical role of the transcription factor NR2F2 in mouse fetal Leydig cell (FLC) differentiation. With elegantly carried out experiments, the authors provide compelling evidence that NR2F2 helps to initiate the differentiation of certain interstitial cells into FLC until these cells mature into functional secretory cells that produce androgen and insulin-like peptide 3 (INSL3). The particular importance of the work comes from the fact that NR2F2 affects FLCs without altering paracrine signals known to be involved in FLC differentiation. The work will be of interest to colleagues studying reproductive development in mammals including humans or the biological functions of the nuclear receptor family.

eLife Assessment

This important work describes results from a set of simulation and empirical studies of a set-up assessing exploratory behavior in a potentially rewarding environment that contains danger. The core idea is that an instrumental agent can be helped to be both effective and safe, thus avoiding excessive danger, during exploratory behavior, if the influence of an independent Pavlovian fear is flexibly gated based on uncertainty. This work is grounded in previous foundational work on Pavlovian control of instrumental choice, and significantly extends prior work showing that the impact of Pavlovian reward biases can be flexibly gated. The conclusion that safe but effective exploration can be achieved based on a flexibly weighted combination of a Pavlovian and an instrumental agent is convincing.

eLife Assessment

This valuable study reports the first characterization of the CG14545 gene in Drosophila melanogaster, which the authors name "Sakura." Acting during germline stem cell fate and differentiation, Sakura is required for both oogenesis and female fertility, although some mechanistic details require further investigation. This solid study presents a wide-ranging and well-controlled characterization of Sakura, and accordingly the findings and associated reagents described will be of use to scientists interested in oogenesis and early development.

eLife Assessment

This study provides important insights into how cryptic pockets play a role in shaping binding preferences of protein-nucleic acid interactions. By combining biochemical assays and state-of-the-art molecular dynamics simulations, mechanism underlying viral protein 35 (VP35) homologs to bind the backbone of double stranded RNA is presented. The evidence is compelling for molecular determinants that suggest two different dsRNA binding modes for VP35 and also underscores the evolutionary importance of these pockets.

eLife Assessment

This important study offers convincing evidence that intra-Golgi transport slows from cis to trans and varies between cargos even within the same cisternae, supporting a more stable compartment model. Using nocodazole-induced ministacks, the authors show cargo-specific transport kinetics with distinct velocities and residence times. These findings refine the cisternal progression model and prompt further investigation into alternative mechanisms, such as rapid partitioning or rim progression. This study will be of interest to cell biologists studying membrane trafficking, Golgi organization, and protein secretion, as well as researchers investigating the mechanisms of organelle dynamics and the molecular basis of intracellular transport.

eLife Assessment

In this important study, the authors conducted atomistic molecular dynamics simulations to probe the interactions between IRE and unfolded peptides. The results help reconcile contradicting experimental findings in the literature and offer mechanistic insights into the activation of the unfolded protein response. The level of evidence is considered solid, although the use of enhanced sampling and more quantitative analysis would further strengthen the conclusions.

eLife Assessment

This work provides one of the first important attempts to look at Drosophila immune responses against bacterial, viral, and fungal pathogens in a way that combines the roles of four major arms in immunity (Imd signaling, Toll signaling, phagocytosis, and melanization) rather than studying them separately. The findings are convincing, and the tools provided can be used as they are, or built upon, in various contexts.

eLife Assessment

This important study reports an advancement in the diagnosis of Animal African Trypanosomosis (AAT), which adapts a CRISPR-based diagnostic tool (SHERLOCK4AAT) to detect different trypanosome species responsible for AAT. The evidence supporting the conclusions is convincing and in line with the current state-of-the-art diagnostics. This study will be of interest to the fields of Epidemiology, Public Health, and Veterinary Medicine.

eLife Assessment

This important study investigates frequency-dependent effects of transcutaneous tibial nerve stimulation (TTNS) on bladder function in healthy humans and, through a computational model, shows that low-frequency stimulation accelerates, and high-frequency delays, the urge to void. The integration of experimental and modeling approaches provides a solid foundation for clinical trials targeting urinary retention. However, concerns were raised about over-interpretation of modest effects and the limited physiological validity of the computational model, especially its mismatch with typical bladder behaviour and lack of quantitative validation.

eLife Assessment

This valuable study provides insights into the structure and function of bacterial contractile injection systems that are present in the cytoplasm of many Streptomyces strains. A convincing high-resolution model of the structure of extended forms of the cytoplasmic contractile injection system assembly from Streptomyces coelicolor is presented, with some investigation of the membrane protein CisA in attachment of the extended assembly to the inner face of the cytoplasmic membrane and the firing of the system. The work expands the current understanding of these diverse bacterial nanomachines.

eLife Assessment

This important study provides information on the TMEM16 family of membrane proteins, which play roles in lipid scrambling and ion transport. By simulating 27 structures representing five distinct family members, the authors captured hundreds of lipid scrambling events, offering insights into the mechanisms of lipid translocation and the specific protein regions involved in these processes. While the data on comparison of scrambling competence is compelling, the evidence for outside-the-groove scramblase activity without experimental validation is missing and is based on a limited set of observed events.

eLife Assessment

This study presents important insights into the regulation of left-right organ formation. By combining genetic perturbation of all three Meteorin genes in zebrafish and timelapse imaging, the authors identify an essential role for this protein family in the establishment of left-right patterning. They provide convincing evidence that Meteorins are required for the morphogenesis of dorsal forerunner cells, the precursors of the left-right organizer (also named Kupffer's vesicle) in zebrafish. In line with this, Meteorins were shown to genetically interact with integrins ItgaV and Itgb1b to regulate dorsal forerunner cell clustering.

eLife Assessment

The study provides a valuable analysis of escape from X-inactivation based on three rare female GTEX-donors with non-mosaic X-inactivation. The methods and analyses are solid and broadly support the authors' claims. Their data are more comprehensive than those presented previously and add significant weight to evidence for which genes are inactivated or escape from X inactivation in humans.

eLife Assessment

This important study uncovers the mechanism of inhibition of a membrane pyrophosphatase by non-hydrolyzable phosphonate substrate analogs. Convincing crystallography, EPR spectroscopy, and functional measurements support the presence of a distinct conformational equilibrium of TmPPase in solution, and further supports the notion of asymmetric inhibitor binding at the active site, while maintaining a symmetric conformation at the periplasmic interface.

eLife Assessment

This study presented valuable findings regarding the basic molecular pathways leading to the cystogenesis of Autosomal Dominant Polycystic Kidney Disease, suggesting BICC1 functions as both a minor causative gene for PKD and a modifier of PKD severity. Although some solid data were supplied to show the functional and structural interactions between BICC-1 and PKD2 and their relevance to the pathogenesis of ADPKD, the characterization of such interactions appear to be incomplete, which renders the specific relevance of these findings for disease etiology unclear.

eLife Assessment

The ratio of nuclei to cell volume is a well-controlled parameter in eukaryotic cells. This important study now substantially advances our understanding of the regulatory relationship between cell size and the number of nuclei by identifying novel players in this process. The evidence supporting the conclusions is compelling, with biochemical assays and state-of-the-art microscopy. The paper will be of broad interest for cell biologists and fungal biotechnologists seeking to understand mechanisms determining cell size and number of nuclei, and why this knowledge is also of significant importance for the production of enzymes, and thus production strains not only of Aspergillus oryzae, but also other industrially used fungi.

eLife Assessment

The manuscript presents a valuable finding that CCDC32, beyond its reported role in AP2 assembly, follows AP2 to the plasma membrane and regulates clathrin-coated pit assembly and dynamics. The authors further suggest that the alpha-helical region of CCDC32 interacts with AP2 via the alpha appendage domain to mediate this function. While live-cell and ultrastructural imaging data are solid, future biochemical studies will be needed to confirm the proposed CCDC32-AP2 interaction.

[Editors' note: this paper was reviewed by Review Commons.]

eLife Assessment

This study provides an in-depth exploration of the impact of X-linked ZDHHC9 gene mutations on cognitive deficits and epilepsy, with a particular focus on the expression and function of ZDHHC9 in myelin-forming oligodendrocytes (OLs). These valuable findings offer insights into ZDHHC9-related X-linked intellectual disability (XLID) and shed light on the regulatory mechanisms of palmitoylation in myelination. The experimental design and analysis of results are solid, providing a reference for further research in this field.

eLife Assessment

This manuscript determines how PA28g, a proteasome regulator that is overexpressed in tumors, and C1QBP, a mitochondrial protein for maintaining oxidative phosphorylation that plays a role in tumor progression, interact in tumor cells to promote their growth, migration and invasion. Additional experiments and analyses that supported the theoretical models for the interaction have been performed in response to the reviews. The overall findings and conceptual framework are important and the evidence is solid. A logical extrapolation of this work is to test the C1QBP mutants using functional assays to determine whether the mutations can decrease the protein stability mediated by the interaction with PA28g.

eLife Assessment

This important study reports solid evidence for the significant role of mother-child neural synchronization and relationship quality in the development of Theory of Mind (ToM) and social cognition. The findings effectively bridge brain development with children's behavior and parenting practices, and will be of interest to researchers studying brain development and social cognition, as well as the general public.

eLife Assessment

This important study presents a compelling theoretical framework for understanding phase separation of membrane-bound proteins, with a focus on the organization of tight junction components. By incorporating non-dilute binding effects into thermodynamic models and validating the model's predictions with in vitro experiments on the tight junction protein ZO-1, the authors provide a quantitative tool that will be of interest for biologists interested in membrane-associated condensates. While further clarification of model assumptions and broader mechanistic context would strengthen the work even further, the combination of theory and experiment here is robust and a key advancement in the field.

eLife Assessment

This fundamental study examines whether synaptic cell adhesion molecules neuroligin 1-3 resident on astrocytes, rather than neurons, exert effects on synaptic structure and function. With compelling evidence, including rigorous validation of neuroligin deletion efficiency in astrocytes and independent confirmation using human neuron-mouse glia co-cultures, the authors report that deletion of neuroligins 1-3 specifically in astrocytes does not alter synapse formation or astrocyte morphology in the hippocampus or visual cortex. This study provides definitive evidence highlighting the specific role of neuronal neuroligins rather than their astrocytic counterparts in synaptogenesis.

eLife Assessment

This fundamental work extends our understanding of the role of TGFβ2 as a modulator of mechanosensing in the eye and identifies the TRPV4 ion channel as a common regulator of Trabecular Meshwork (TM) contractility and pathological OHT and the data and evidence provided are convincing. This work will clearly be of interest to researchers investigating the role of mechanosensors in the TM and may underpin future research into treatments that aim to lower intra ocular pressure. This work will additionally be of interest to the growing field of researchers investigating the regulation of force sensing via ion channels and their roles in health and disease, in particular the ion channel TRPV4.

eLife Assessment

This important study presents a pipeline for discovering cooperative transcription factor (TF) interactions that regulate development, and applies this pipeline in a systematic investigation of TF co-regulation in 11 human embryonic tissues. The authors provide overall solid bioinformatics and experimental support for their findings: although they make a convincing argument for the role of TEAD factors as co-repressors of regulatory activity with tissue-specific TFs, other aspects of the study would benefit from additional validation. This work would be of interest to cell biologists focused on development or on discovery of TF relationships.

eLife Assessment

There is a growing interest in understanding the individuality of animal behaviours. In this article, the authors build and use an impressive array of high throughput phenotyping paradigms to examine the 'stability' (consistency) of behavioural characteristics in a range of contexts and over time. They find that certain behaviours are individualistic and persist robustly across external stimuli while others are less robust to these changing parameters. The data, while extensive are incompletely analysed/explained. With more appropriate statistical methods adopted, the findings would have important implications for the study of individual variability.

eLife Assessment

This important study tests the development of motor reinforcement learning from toddlerhood to adulthood, using a large online sample. They show that learning improves with age in a task that, like real-life movement, involves a continuous range of response options and probabilistic rewards, and link this shift to reduced movement variability and more efficient feedback-based learning through behavioural modeling. Simplifying the task with discrete actions and deterministic outcomes boosted younger children's performance, suggesting early learning is limited by spatial and probabilistic processing. The evidence is convincing, although future work may investigate more naturalistic movement.

eLife Assessment

This study provides an important set of analyses and theoretical derivations to understand the mechanisms used by recurrent neural networks (RNNs) to perform context-dependent accumulation of evidence. The results regarding the dimensionality and neural dynamical signatures of RNNs are convincing and provide new avenues to study the mechanisms underlying context-dependent computations. This manuscript will be of interest to a broad audience in systems and computational neuroscience.

eLife Assessment

The manuscript contains important findings regarding inflammatory macrophage subsets that have theoretical and/or practical applications beyond the field of rheumatology. The authors demonstrate with compelling evidence the effects of PGE2 on TNF signaling. This work will be of broad interest to immunologists and cell biologists.

eLife Assessment

The authors study the context of the skeletal remains of three individuals and associated sediment samples to conclude that the hominin species Homo naledi intentionally buried their dead. Demonstration of the earliest known instance of intentional funerary practice – with a relatively small-brained hominin engaging in a highly complex behavior that has otherwise been observed from Homo sapiens and Homo neanderthalensis – would represent a landmark finding. The authors have revised their manuscript extensively in light of the reviews of their initial submission, with improved illustration, context, discussion, and theoretical frameworks, leading to an improved case supporting their conclusion that Homo naledi intentionally buried their dead. One of the reviewers concludes that the findings convincingly demonstrate intentional burial practices, while another considers evidence for such an unambiguous conclusion to be incomplete given a lack of definitive knowledge around how the hominins got into the chamber. We look forward to seeing the continued development and assessment of this hypothesis. It is worth noting that the detailed reviews (both rounds) and comprehensive author response are commendable and consequential parts of the scientific record of this study. The editors note that the authors' response repeatedly invokes precedent from previous publications to help justify the conclusions in this paper. While doing so is helpful, the editors also note that scientific norms and knowledge are constantly evolving, and that any study has to rest on its own scientific merit.

eLife Assessment

The songbird vocal motor nucleus HVC contains cells that project to the basal ganglia, the auditory system, or to downstream vocal motor structures. In this fundamental study, the authors conduct optogenetic circuit mapping to clarify how four distinct inputs to HVC act on these distinct HVC cell types. They provide compelling evidence that all long range projections engage inhibitory circuits in HVC and can also exhibit cell-type specific preferences in monosynaptic input strength. Understanding HVC at this microcircuit level is critical for constraining models of song learning and production.

eLife Assessment

The study reports valuable findings from a very rich EEG-fMRI dataset, including 107 participants, which was collected during nocturnal naps. Using overall solid methods, the authors link activity in memory-related brain regions (e.g., hippocampus, thalamus, and medial prefrontal cortex), and their functional connectivity to the occurrence of canonical sleep rhythms (spindles and slow oscillations) in non-rapid eye movement sleep. This work will be of broad interest to sleep and memory researchers and beyond.

eLife Assessment

The findings of this study are valuable, offering insights into the neural representation of reversal probability in decision-making tasks, with potential implications for understanding flexible behavior in changing environments. The study contains interesting comparisons between neural data and models, including evidence for partial consistency with line attractor models in this probabilistic reversal learning task. However, it remains incomplete due to issues related to how the RNN training and the analysis of its dynamics, which renders the evidence as not complete.

eLife Assessment

This valuable paper uses a quantitative modeling approach to explore a well-studied transition in motor behavior in the nematode C. elegans. The authors provide solid evidence that this transition, which has been considered by many in the field to be a two-state behavior, can instead be described as a process whose parameters are smoothly modulated within a single state. This finding provides insight into the relationships between latent internal states and observable behavioral states, and suggests that relatively simple neuronal mechanisms can drive behavioral sequences that appear more complex.

eLife Assessment

This study provides valuable insights into the evolutionary conservation of sex determination mechanisms in ants by identifying a candidate sex-determining region in a parthenogenetic species. The strength of evidence is solid, using genomic analyses to identify differences in heterozygosity between females and diploid males, though the conclusions are limited by the lack of functional analysis.

eLife Assessment

This manuscript presents an interesting new framework (VARX) for simultaneously quantifying effective connectivity in brain activity during sensory stimulation and how that brain activity is being driven by that sensory stimulation. The reviewers thought the model was original and its conclusion that intrinsic connectivity is reduced (rather than increased) during sensory stimulation is very interesting, but that for ideal performance, one must specify all sensory features in the model, which is not possible. Overall, however, this work is important with convincing evidence for its conclusions - it will be of interest to neuroscientists working on brain connectivity and dynamics.

eLife Assessment

This valuable work presents an interpretable protein-DNA Energy Associative (IDEA) model for predicting binding sites and affinities of DNA-binding proteins. While the method is convincing, it requires some adaptation for application to different proteins. The IDEA method is available and can be potentially used for predicting genome-wide protein-DNA binding sites.

eLife Assessment

In this important paper, the authors use single-cell RNA sequencing to understand post-mitotic cone and rod developmental states and identify cone-specific features that contribute to retinoblastoma genesis. The authors report findings that have practical implications for retinal development, gene expression, and cell fate specification. The evidence is compelling as the experimental design and analysis are exceptionally rigorous.

eLife Assessment

This useful manuscript addresses a stability issue for long-term chronically implanted array recordings and electrolytic lesioning, which is relevant to both basic science and translational research. The authors provide a systematic scanning electron microscopy (SEM) of explanted arrays, evaluating electrode damage and sharing extensive datasets accessible through interactive plots. The strength of the evidence is solid, but it can be improved by performing additional analyses on complementary neurophysiology, functional, or histological data.

eLife Assessment

This fundamental study demonstrates how a left-right bias in the relationship between numerical magnitude and space depends on brain lateralization. The evidence is compelling, and the manuscript could be strengthened by improving its contextualization, presentation, and discussion. The results will be of interest to researchers studying numerical cognition, brain lateralization, and cognitive brain development more broadly.

eLife Assessment

This manuscript develops a theoretical model of osmotic pressure adaptation in microbes by osmolyte production and wall synthesis. The prediction of a rapid increase in growth rate on osmotic shock is experimentally validated using fission yeast. By using phenomenological rules rather than detailed molecular mechanisms, the model can potentially apply to a wide range of microbes, providing important insights that would be of interest to the wider community studying the regulation of cell size and mechanics. The level of coarse-graining and the assumptions and limitations of the model have been well described, providing a convincing foundation for making predictions. However, further experimental work on the validity of the core assumptions across a range of microbial organisms is needed to assess the universality of the model.

eLife Assessment

This paper presents important information about potential Homo naledi-associated markings discovered on the walls of the Hill Antechamber of the Rising Star Cave system, South Africa. If confirmed, the antiquity, intentionality, and authorship of the reported markings will have profound archaeological implications, as such behaviors are otherwise widely considered to be unique to our species, Homo sapiens. This report concerns preliminary findings and as it stands the study is incomplete, with further work needed in the future to support the claims about the anthropogenic nature, age, and author of the engravings.

eLife Assessment

This important study uses Mendelian Randomization to provide evidence that early-life reproductive phenotypes (i.e., age at onset of menarche and age at first birth) have a significant impact on numerous health outcomes later in life. The empirical evidence provided by the authors supporting the antagonistic pleiotropy theory is solid. Theories of aging should be empirically tested and this study provides a good first step in that direction.

eLife Assessment

This study on the effect of the trophic factor BDNF upon dental cells is an understudied subject that is relevant to dental regeneration and repair. Given that the topic is new and has not been covered previously, the report is a useful foray into a new area of investigation, although several experimental results could be strengthened. The connection of BDNF and dental health is a solid attempt in potentially translating trophic factor signaling clinically, which has been stymied in past efforts.

eLife Assessment

A combination of molecular dynamics simulation and state-of-the-art statistical post-processing techniques provided valuable insight into GPCR-ligand dynamics. This manuscript provides solid evidence for differences in the binding/unbinding of classical cannabinoid drugs from new psychoactive substances. The results could aid in mitigating the public health threat these drugs pose.

eLife Assessment

This fundamental study investigates the role of polyunsaturated fatty acids (PUFAs) in physiology and membrane biology, using a unique model to perform a thorough genetic screen that demonstrates that PUFA synthesis defects cannot be compensated for by mutations in other pathways. These findings are supported by compelling evidence from a high quality genetic screen, functional validation of their hits, and lipid analyses. This study will appeal to researchers in membrane biology, lipid metabolism, and C. elegans genetics.

eLife Assessment

This paper provides a useful new theory of the hallucinatory effects of psychedelics. The authors present convincing evidence that a computational model trained with the Wake-Sleep algorithm can reproduce some features of hallucinations by varying the strength of top-down connections in the model, but discussion of the model's relationships to the psychedelics and sleep literatures is incomplete. The work will be of interest to researchers studying hallucinations or offline activity and learning more broadly.

eLife Assessment

This study proposes a potentially useful improvement on a popular fMRI method for quantifying representational similarity in brain measurements by focusing on representational strength at the single trial level and adding linear mixed effects modeling for group-level inference. The manuscript demonstrates increased sensitivity with no loss of precision compared to more classic versions of the method. However, the framing of the work with respect to these prior approaches is incomplete, several assumptions are insufficiently motivated, and it is unclear to what extent the approach would generalize to other paradigms.

eLife Assessment

In this valuable study, Wandler et al. provide convincing theoretical evidence for alternate mechanisms of rhythm generation by CPGs. Their model shows that cell-type-specific connectivity and a dominant inhibitory drive could underlie rhythm generation. Excitatory input could act to enhance the frequency range of these rhythms. This modeling study could motivate further experimental investigation of these mechanisms to understand CPG rhythmogenesis.

eLife Assessment

This important work compares the size of two brain areas, the amygdala and the hippocampus, across 12 species belonging to the Macaca genus. The authors find, using a convincing methodological approach, that amygdala - but not hippocampal - volume varies with social tolerance grade, with high tolerance species showing larger amygdala than low tolerance species of macaques. Interestingly, their findings also suggest an inverted developmental effect, with intolerant species showing an increase in amygdala volume across the lifespan, compared to tolerant species exhibiting the opposite trend. Overall, this paper offers new insights into the neural basis of social and emotional processing.

eLife Assessment

This is a useful tool for code-less analysis of patterns in cell migratory behaviours in vivo using intravital microscopy data and allows correlation with spatial features of the tumour microenvironment. There is a need for these tools to make quantitative analysis, comparison and interpretation of complex cell tracking data more accessible and evidence is provided of its applicability to tracks generated by both proprietary and open tracking software. However, it is incomplete due to limitations imposed by the assumptions that apply to the statistical tests employed.

eLife Assessment

This important study investigates the role of Drp1 in early embryo development. The authors have addressed most of the original comments and the work now presents convincing evidence on how this protein influences mitochondrial localization and partitioning during the first embryonic divisions. The research employs the Trim-Away technique to eliminate Drp1 in zygotes, revealing critical insights into mitochondrial clustering, spindle formation, and embryonic development.

eLife Assessment

This valuable study provides a novel framework for leveraging longitudinal field observations to examine the effects of aging on stone tool use behaviour in wild chimpanzees. The methods and results are robust providing solid evidence of the effects of old age on nut cracking behaviour at this field site. Despite the low sample size of five individuals, this study is of broad interest to ethologists, primatologists, archaeologists, and psychologists.

eLife Assessment

This important study explores the mechanisms underlying the maintenance of cell surface protein levels. The authors present solid evidence to support their claims, though the addition of certain validation experiments could have further strengthened the conclusions. This work will be of particular interest to cell biologists focused on membrane trafficking.

eLife Assessment

This valuable study uses AlphaFold2 to guide the structural modelling of different states of the human voltage-gated potassium channel KV11.1, a key pharmacological drug target. Follow-up molecular dynamics and drug-docking simulations, combined with experimental characterization, offer convincing evidence supporting the models. The work shows potential for improving drug potency predictions in ion channel pharmacology.

eLife Assessment

In this important manuscript, the authors reveal novel findings on the role of exosomes in regulating filopodia formation. Filopodia are crucial for various cellular processes, including migration, polarization, directional sensing, and the formation of neuronal synapses. The authors convincingly demonstrate that exosomes, particularly those enriched with the protein THSD7A, play a significant role in promoting filopodia formation in both cancer cells and neurons.

eLife Assessment

Building on previous structural studies, this work provides valuable new insights into the architecture of the autophagy initiation complex, comprising ULK1, ATG13, and FIP200. The authors present their findings with solid supporting evidence, making this study a significant contribution to the autophagy field.

eLife Assessment

This important study investigates how hummingbird hawkmoths integrate stimuli from across their visual field to guide flight behavior. Cue conflict experiments provide solid evidence for an integration hierarchy within the visual field: hawkmoths prioritize the avoidance of dorsal visual stimuli, potentially to avoid crashing into foliage, while they use ventrolateral optic flow to guide flight control. The paper will be of broad interest to enthusiasts of visual neuroscience and flight behavior.

eLife Assessment

Using a unique cerebellar disruption approach in non-human primates, this study provides valuable new insight into how cerebellar inputs to the motor cortex contribute to reaching. The findings convincingly demonstrate that reaching movements following cerebellar disruption slow down because of both an acute deficit in producing muscle activity as well as a progressive decline in compensating for limb dynamics. This work will be of interest to neuroscientists and clinicians interested in cerebellar function and pathology.

eLife Assessment

The work presents a valuable extension of qFit-ligand, a computational method for modeling conformational heterogeneity of ligands in X-ray crystallography and cryo-EM density maps. The authors provide solid evidence of improved capabilities through careful validation against the previous version, particularly in expanding ligand sampling within conformational space. Such improvements suggest practical utility for challenging applications, including macrocyclic compound modeling and crystallographic drug fragment screening.

eLife Assessment

This important study reports a reanalysis of one experiment of a previously-published report to characterize the dynamics of neural population codes during visual working memory in the presence of distracting information. This paper presents solid evidence that working memory representations are dynamic and distinct from sensory representations of intervening distractions. This research will be of interest to cognitive neuroscientists working on the neural bases of visual perception and memory.

eLife Assessment

In this important study, the authors have performed a zebrafish drug screen to identify suppressors of atherogenic lipoproteins. They utilize a well-established LipoGlo assay to find molecules that modulate these lipoproteins, identifying 49 potential hits. They perform some validation experiments, including studies linking enoxolone to its likely inhibitory effect on a specific transcription factor, HNF4alpha. Overall, the results are convincing and robust, and will open up new areas of exploration for those investigators interested in in vivo lipid biology.

eLife Assessment

This study provides useful information on the impact of Lamin A/C knockdown on gene expression using RNA-Seq analysis. In addition, the impact of Lamin A/C knockdown on telomere dynamics is explored using live cell imaging. The conclusions, however, are inadequately supported by the data presented. Weaknesses include excessive reliance on gene ontology analysis without further validation of direct versus indirect effects, use of only one shRNA, which may have off target effects, validation of knockdown only from gene expression rather than protein levels, lack of discussion on previous studies showing the presence of Lamin A/C in the nuclear interior among others.

eLife Assessment

This study reveals that PRMT1 overexpression drives tumorigenesis of acute megakaryocytic leukemia (AMKL) and that targeting PRMT1 is a viable approach for treating AMKL. After revision, both reviewers found that these findings are important and that the data supporting these findings are convincing. Furthermore, these findings likely have significant implications for the treatment of AMKL with PRMT1 overexpression in the future.

eLife Assessment

This study presents valuable findings on the regulation of survival and maintenance of brain-resident immune cells called microglia. Using compelling and sophisticated genetic tools, the authors demonstrate a gene dosage-dependent mechanism using which microglia are eliminated. This research on cell competition and survival will be of broad interest to the cell biology community.

eLife Assessment

This fundamental work has the potential to advance our understanding of brain activity using electrophysiological data, by proposing a completely new approach to reconstructing EEG data that challenges the assumptions typically made in the solutions to Maxwell’s equations. Convincing evidence for the superior spatio-temporal resolution of this method is provided through a number of experiments, including simultaneous FMRI/EEG acquisitions. This work will be of broad interest to neuroscientists and neuroimaging.

eLife Assessment

The authors investigated the mechanisms underlying the pause in striatal cholinergic interneurons (SCINs) induced by thalamic input, identifying that Kv1 channels play a key role in this burst-dependent pause. The experimental evidence is convincing.<br /> The study provides important mechanistic insights into how burst activity in SCINs leads to a subsequent pause, highlighting the involvement of D1/D5 receptors.

eLife Assessment

This timely and important study used functional near-infrared spectroscopy hyperscanning to examine the neural correlates of how group identification influences collective behavior. The work provides solid evidence to indicate that the synchronization of brain activity between different people underlies collective performance and that changes in brain activity patterns within individuals may, in turn, underlie this between-person synchrony, although the order in which different task stages were completed could not be counter-balanced. This study will be of interest to researchers investigating the neuroscience of social behaviour.

eLife Assessment

This manuscript presents a clever and powerful approach to examining differential roles of Nav1.2 and Nav1.6 channels in excitability of neocortical pyramidal neurons, by engineering mice in which a sulfonamide inhibitor of both channels has reduced affinity for one or the other channels. Overall, the results in the manuscript are compelling and give important information about differential roles of Nav1.6 and Nav1.2 channels. Activity-dependent inactivation of NaV1.6 was also found to attenuate seizure-like activity in cells, demonstrating the promise of activity-dependent NaV1.6-specific pharmacotherapy for epilepsy.

eLife Assessment

This study presents a valuable investigation into how heavy metal stress may have influenced the domestication of maize from its wild ancestor, teosinte parviglumis, focusing on specific ATPase genes with proposed roles in heavy metal homeostasis. The evidence supporting the main claims is incomplete, with suggestive but not definitive data linking gene function to domestication traits, and limited environmental context for the hypothesized selection pressures. While the work introduces an interesting model connecting environmental stress responses to evolutionary transitions and highlights underexplored aspects of teosinte plasticity, the conclusions would benefit from more comprehensive analyses such as transcriptomics, a broader survey of loci, and stronger paleoenvironmental validation. The study will be of interest to researchers in plant evolution and domestication, but currently lacks the analytical depth to fully support its central hypothesis.

eLife Assessment

This study presents valuable findings about daily rhythm changes of the Drosophila melanogaster adult gut metabolome, which is shown to be dependent on the circadian clock genotype, dietary regime and composition, and gut microbiota. The phenomena observed are supported by convincing experimental evidence. The general descriptive approach limits the power of the proposed conclusions. The work will be of interest to a broad range of physiology specialists

eLife Assessment

This study introduces a novel and broadly applicable metric-phenological lag-to partition the effects of spring warming from other abiotic constraints on plant phenology. While the dataset is extensive and the analytical framework is valuable conceptually, the manuscript lacks clarity in its aims and justification for the new metric, and key results are underdeveloped or poorly visualized. The strength of evidence is moderate to solid, but revisions are needed to clarify the study's contribution and improve interpretability.

eLife Assessment

This is a potentially important study that explores the relevant range of parameter values for calibration and validation of cardiac electromechanics in ventricular models. Although much of the work presented is solid, the evidence provided to support the authors' key scientific claims is incomplete, especially as it relates to the emphasis on standardized validation and verification approaches. Notably, the level of model personalization presented in this work falls short of the threshold for what could reasonably be called a "digital twin", even by the relatively relaxed standards that have emerged in computational physiology and related fields in recent years.

eLife Assessment

This study presents significant and novel insights into the roles of zinc in mammalian meiosis/fertilization events. These findings are useful to our understanding of these processes. The evidence presented is solid, with experiments being well-designed, carefully described, and interpreted with appropriate rigor.

eLife Assessment

Inspired by bee's visual behavior, the goal of the manuscript is to develop a model of visual scanning, visual processing and learning to recognize visual patterns. In this model, pre-training with natural images leads to the formation of spatiotemporal receptive fields that can support associative learning. Due to an incomplete test of the necessity and sufficiency of the features included in the model, it cannot be concluded that the model is either the "minimal circuit" or the most biologically plausible circuit of this system. With a more in-depth analysis, the work has the potential of being important and very valuable to both experimental and computational neurobiologists.

eLife Assessment

In their valuable study, Bracey et al. investigate how microtubule organization within pancreatic islet beta cells supports optimal insulin secretion. Using a combination of live imaging and photo-kinetic assays in an in vitro culture system, they provide compelling evidence that kinesin-1-mediated microtubule sliding, which plays critical roles in neurons and embryos, also plays a critical role in forming the sub-membranous microtubule band in response to glucose in beta cells. This work will be of interest to cell biologists studying cytoskeletal dynamics and organelle trafficking, as well as to translational biologists focused on diabetes.

eLife Assessment

This fundamental study provides new insights into the maturation of ribbon synapses in zebrafish neuromast hair cells. Live-cell imaging and pharmacological and genetic manipulations together provide compelling evidence that the formation of this synaptic organelle is a dynamic process involving the fusion of presynaptic elements and microtubule transport, though the evidence that ribbon precursors move in a directed motion toward the active zone is less persuasive. These findings will be of interest to neuroscientists studying synapse formation and function and should inspire further research into the molecular basis for synaptic ribbon maturation.

eLife Assessment

This useful manuscript describes cryo-EM structures of archaeal proteasomes that reveal insights into how occupancy of binding pockets on the 20S protease regulates proteasome gating. The evidence supporting these claims is convincing, although inclusion of more quantitative comparisons would help strengthen the conclusions. This work will be of special interest to researchers interested in proteasome structure and regulation.

eLife Assessment

The findings in this manuscript are fundamental because they identify an entry receptor MYL3 that belongs to the myosin family as a possible target that could inhibit a virus that has a high impact on aquaculture. The evidence is convincing as it contains strong in vitro and in vivo data that support their conclusions; however, studies on the presence of MYL3 in NNV target tissues will further strengthen their claims

eLife Assessment

This valuable study provides in-vivo evidence that CCR4 regulates the early inflammatory response during atherosclerotic plaque formation. The authors propose that altered T-cell response plays a role in this process, shedding light on mechanisms that may be of interest to medical biologists, biochemists, cell biologists, and immunologists. The work is currently considered incomplete pending textual changes and the inclusion of proper controls.

eLife Assessment

This study presents a new, fundamental finding to the field interested in recurrent processing and its neuromodulatory underpinnings, finding unexpectedly that memantine (blocking NMDA-receptors) enhances the decoding of features thought to rely on NMDA-receptors. This interesting, compelling result identifies new directions for researchers studying consciousness, sensory processing, attention, and neurotransmitters.

eLife Assessment

This is a fundamental cell biological study of host responses during symbiotic microbial infection of plants. Compelling imaging-based approaches using genetically encoded cell cycle markers show that in Medicago truncatula root cortex cells, early rhizobial infection events are associated with cell-cycle re-entry, but once the infection is established, host cells exit the cell cycle. The work will be of interest to a wide range of readers working in fields from development and cell biology to plant-microbe interactions.

eLife Assessment

In this convincing work by Yamaguchi et al. the cryo-EM structure of the heterohexameric 3:3 LGI1-ADAM22 complex is presented. The findings suggest that LGI1 can cluster ADAM22 in a trimeric fashion. The clustering of cell surface proteins is important in controlling signaling in the nervous system. This new version of the manuscript has been improved substantially and the figures have been enhanced and clarified.

eLife Assessment

This solid study assesses a mitochondrial polymerase inhibitor in combination with the BCL-2 inhibitor venetoclax, with the aim to increase the elimination of acute myeloid leukemia. It provides valuable findings of combinatorial efficacy using preclinical models in vitro and in vivo, confirming the overall importance of targeting oxidative phosphorylation to overcome venetoclax resistance in acute myeloid leukemia, and could be strengthened through mechanistic studies demonstrating on target effects and pharmacodynamic efficacy in vivo. The study is of interest to hematologists because it addresses a key biomedical issue in acute myeloid leukemia (venetoclax resistance) and provides data regarding the safety and activity of a novel inhibitor of the mitochondrial polymerase in combination with venetoclax.

eLife Assessment

The study presents extensive gene expression profiling and bioinformatic analyses, offering insights into the roles of fibroblasts in cardiac development. The large volume of scRNA-seq data is both compelling and important to the scientific community. All three reviewers agree that the revised manuscript represents a significant improvement and addresses most, if not all, of their previous concerns. The reviewers also acknowledge that detailed mechanistic studies on how fibroblast-derived collagen regulates myocardial and coronary vasculature development are beyond the scope of the current study.

eLife Assessment

This work demonstrates the therapeutic potential of recombinant human PDGF-AB/BB proteins in alleviating the senescent signatures of primary human intervertebral disc cells. The study represents a fundamental, significant advance in the treatment of intervertebral disc degeneration through the suppression of senescence. The strength of evidence supporting these conclusions is compelling, as it is primarily based on transcriptomic analysis and direct protein measurements from relatively homogeneous cell populations. This work will be of interest to spine basic scientists and clinicians, as well as to musculoskeletal scientists more broadly. The revised manuscript adds greater clarity, and the impact of the study is greatly enhanced.

eLife Assessment

This study presents important new insights linking obesity to kidney disease using a Drosophila model. A series of compelling experiments demonstrate that a high-fat diet induces excretion of a leptin-like JAK-STAT ligand from fat body, driving the adipose-nephrocyte axis through activated JAK-STAT signaling and subsequently causing a functional defect in nephrocytes. The approach using combination of genetic tools and pharmacological intervention is solid and confirms the mechanistic link, together with phenotypic analysis that further supports the authors conclusions.

eLife Assessment

Using microscopy experiments and theoretical modelling, the authors present convincing evidence of cellular coordination in the gliding filamentous cyanobacterium Fluctiforma draycotensis. The results are fundamental for the understanding of cyanobacterial motility and the underlying molecular and mechanical pathways of cellular coordination.

eLife Assessment

This fundamental work by Yamamoto and colleagues advances our understanding of how positional information is coordinated between axes during limb outgrowth and patterning. They provide solid evidence that the dorsal-ventral axis feeds into anterior-posterior signaling, and identify the responsible molecules by combining transplantations with molecular manipulations. This work will be of broad interest to regeneration, tissue engineering, and evolutionary biologists.

eLife Assessment

This valuable study investigates how stochastic and deterministic factors are integrated during cellular decision-making, particularly in situations where cells differentiate into distinct fates despite being exposed to the same environmental conditions. The authors present convincing evidence that gene expression variability contributes to the robustness of cell fate decisions in D. discoideum, which sheds light into the role of stochasticity during cell differentiation.

eLife Assessment

The manuscript explores how bacterial evolution in the presence of lytic phages modulates b-lactams resistance and virulence properties in methicillin-resistant Staphylococcus aureus (MRSA). This important work improves our knowledge of how mutation in genes required for phage infection confers sensitivity to b-lactams and alter virulence properties. Altogether, the findings are convincing.

eLife Assessment

The manuscript explores how bacterial evolution in the presence of lytic phages modulates b-lactams resistance and virulence properties in methicillin-resistant Staphylococcus aureus (MRSA). The work is valuable as it identifies underlying mutations that may confer sensitivity to b-lactams and alter virulence properties. While the findings are generally convincing, additional experiments linking how particular mutations regulate phenotypic changes are required to improve the work mechanistically.

eLife Assessment

The study by Power and colleagues is important, as elucidating the dynamic immune responses to photoreceptor damage in vivo potentiates future work in the field to better understand the disease process. The evidence supporting the authors' claims is compelling.

eLife Assessment

This study shows that a peptide called galanin can decrease or increase seizure activity in experimental models of seizures depending on the model. The authors use zebrafish and several methods to address the effects of galanin. The study will be useful to researchers who use zebrafish as experimental animals and who are interested in how peptides like galanin regulate seizures. However, the strength of evidence was considered incomplete at the present time due to several limitations of the results.

Editors Assessment:

This Data Release paper presents the first genome assembly of the lemon sole (Microstomus kitt), a commercially important flatfish found in European coastal waters. It is also interesting that this work was carried out in a University course setting involving the students. The resulting chromosome-level genome was assembled using long-read PacBio HiFi sequencing and the Hi-C technique. The 628 Mbp reference (which is consistent with other Pleuronectidae fish species) is assembled into 24 chromosome-length scaffolds with high completeness, achieving a scaffold N50 of 27.2 Mbp. Peer review and data curation made the author clarify a few points and share all of the data and results in an open and well curated manner. The annotated genome of the lemon sole, with its high continuity, should therefore provide important reference data for future population genetic analyses and conservation strategies of this organism.

This evaluation refers to version 1 of the preprint

eLife Assessment

This fundamental study identified a novel role of NOLC1 in regulating p53 nuclear transcriptional activity and p53-mediated ferroptosis in gastric cancer. After major revisions, the evidence supporting the conclusions is solid. However, some new experiments are needed to draw more robust conclusions regarding the ferroptosis-associated studies.

eLife Assessment

This manuscript describes an important finding of the transcriptional control of a chimeric gene transfer agents (GTA) cluster in Bartonella by a processive anti-termination factor (BrrG). The evidence provided is convincing. This manuscript will interest researchers working on transcriptional regulation, horizontal gene transfer, and phages.